Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unlike large-vessel endothelial cells in cell culture, cardiac microvascular endothelial cells (CMEC) isolated from adult rat ventricular muscle exhibit little detectable constitutive nitric oxide (NO) synthase activity after isolation in vitro but respond to specific combinations of inflammatory mediators with an increase in inducible NO synthase (iNOS; type 2 NO synthase) activity. CMEC iNOS is induced by soluble inflammatory mediators in lipopolysaccharide-activated rat alveolar macrophage-conditioned medium at 24 hours, and this induction can be partially prevented by either interleukin-1 (IL-1) receptor antagonist or a polyclonal anti-rat tumor necrosis factor-alpha (TNF-alpha) antiserum. Interferon-gamma (IFN-gamma), which by itself does not induce iNOS in CMEC, potentiates and accelerates iNOS induction by IL-1 beta. Transforming growth factor-beta (TGF-beta) decreases iNOS activity, protein content, and mRNA abundance in IL-1 beta- and IFN-gamma-pretreated CMEC. To determine whether NO released by CMEC would affect myocyte contractile function in vitro, freshly isolated ARVM were allowed to settle onto confluent, serum-starved CMEC that had been pretreated for 24 hours with IL-1 beta, a cytokine that alone does not affect myocyte contractile function in vitro. Baseline contractile amplitude, at 2 Hz and 37 degrees C, of myocytes in heterotypic culture with IL-1 beta-pretreated CMEC was not different from that of myocytes in control, homotypic myocyte cultures. However, cocultured myocytes exhibited decreased contractile responsiveness to 2 nmol/L isoproterenol compared with control cells, and this could be reversed by the addition of 1 mmol/L NG-monomethyl-L-arginine, an inhibitor of NOS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contractile responsiveness of ventricular myocytes to isoproterenol is regulated by induction of nitric oxide synthase activity in cardiac microvascular endothelial cells in heterotypic primary culture. 754 25

A nitric oxide (NO) synthase (NOS) can be induced in both astrocytes and cerebral endothelial cells with a combination of interleukin-1 beta/interferon-gamma or lipopolysaccharide/interferon-gamma, respectively. Exogenous NO, either from the chemical donor spermine NONOate or from activated astrocytes, affected the expression of inducible NOS in cerebral endothelial cells. In cerebral endothelial cells pretreated with spermine NONOate the induction of NOS was reduced, as revealed by mRNA expression and nitrite accumulation. Cytokine-treated astrocytes generating NO and placed in close proximity to endothelial cells decreased the expression of NOS induced by cytokines in endothelial cells. In addition, it was apparent that cytokine-activated astrocytes released a factor(s) that initiated transcriptional induction of NOS in cerebral endothelium. This suggests that astrocytes activated by cytokines in vivo could influence expression of inducible NOS in cells of the adjacent microvasculature.
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PMID:Expression of inducible nitric oxide synthase in cerebral endothelial cells is regulated by cytokine-activated astrocytes. 754 34

Evidence has previously been presented for an immunomodulatory role of a soluble activity, designated as tumor-derived recognition factor (TDRF), which was produced constitutively by P815 mastocytoma, L 1210 leukemia and other murine tumor targets. TDRF synergized with IFN-gamma and IL-2 to promote TNF-alpha and mRNA synthesis and release by murine macrophages for increased autocrine induction of nitric oxide (NO)-mediated tumor cytotoxicity. We have now further assessed the modulatory role of TDRF on TNF-alpha, TNF receptors (TNF-R) and NOS mRNA synthesis. Macrophages activated by INF-gamma priming and triggering by rTNF-alpha bacterial lipopolysaccharide (LPS) of IL-2 evoked greater NO generation in the presence than in the absence of L1210 targets. TDRF-containing culture fluid from L1210 targets was subsequently confirmed to synergize with IFN-gamma and rTNF-alpha, LPS or IL-2 triggering agents to promote increased TNF-alpha mRNA for autocrine induction of NOS mRNA synthesis with resultant augmentation of NO generation. IFN-gamma selectively upregulated TNF-R1 mRNA expression, whereas either IL-2 or LPS upregulated only TNF-R2 mRNA expression. TDRF combined with IFN-gamma to further upregulate TNF-R1 mRNA and with either IL-2 or LPS to further upregulate TNF-R2, mRNA expression. These findings indicate that TDRF activity synergizes with either IL-2 or LPS triggering agents for enhanced activation of IFN-gamma-primed macrophages by promotion of TNF-alpha and TNF-R mRNA synthesis for autocrine induction of NOS with resultant increased NO-mediated tumor cytotoxicity.
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PMID:Tumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity. 754 21

Immunohistochemical studies have shown expression of two different isoforms of NOS in the juxtaglomerular apparatus (JGA). Antibodies to a Ca(++)-calmodulin dependent isoform purified from rat brain (B-NOS) label the macula densa cells whereas antibodies to an isoform purified from rat aortic smooth muscle cells in culture (VSM-NOS) induced with lipopolysaccharide and interferon gamma label the afferent arteriole. Since dietary salt intake and angiotensin II (Ang II) are determinants of renal NO generation, we have tested the hypothesis that salt intake can regulate the immunohistochemical expression of these NOS isoforms through an effect of Ang II. In 4 of 5 paired studies, the immunostaining for both B-NOS and VSM-NOS was more intense in rats that had received a low salt (LS), compared to a high salt (HS), diet. Infusion of the Ang II type 1 (AT1) receptor antagonist, losartan, enhanced the intensity of immunoreactive staining for both isoforms. In conclusion, the immunohistochemical expression of NOS isoforms in the JGA is increased by dietary salt restriction; this effect cannot be ascribed to Ang II acting on type 1 receptors.
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PMID:Expression of immunoreactive nitric oxide synthase isoforms in rat kidney. Effects of dietary salt and losartan. 754 16

Mice pre-exposed to cisplatin increased their production of nitric oxide (NO) when treated with lipopolysaccharide (LPS). Peritoneal macrophages, isolated from mice 11 days after cisplatin treatment and cultured with LPS plus IFN-gamma, increased NO production, whereas the macrophages isolated 2 days after cisplatin treatment decreased it. In both cases, NO was not produced without immunostimulant(s). Northern and Western Blot analysis showed that macrophages exposed to cisplatin for 11 days increased production of mRNA and protein expression of inducible nitric oxide synthase (iNOS). THis result indicated that macrophages became more sensitive to LPS and IFN-gamma when they were exposed to cisplatin in vivo. Peritoneal macrophages, when activated with LPS plus IFN-gamma and then cocultured with several tumor cells, exhibited cytotoxic activity against both cisplatin-sensitive and cisplatin-resistant tumor cells. There was no difference in cytotoxicity between the paired cells. Under the same experimental condition, macrophages that were exposed to cisplatin for 11 days had significantly increased their cytotoxicity to the tumor cells. This cytotoxic activity was inhibited by the NOS inhibitor NG-monomethyl-L-arginine, indicating that NO is a major effector for macrophage-mediated tumor cell killing. Treatment of tumor cells with S-nitroso-N-acetylpenicillamine, a NO-generating compound, showed the similar tumoricidal effect. These data demonstrated that injection of cisplatin into the mice can enhance the sensitivity of macrophages to the subsequent treatment of immunostimulant(s) for effective tumor cell killing through enhanced NO production.
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PMID:In vivo cisplatin-exposed macrophages increase immunostimulant-induced nitric oxide synthesis for tumor cell killing. 758 26

Recent evidence suggests that the production of nitric oxide (NO) may have important roles in the regulation of osteoblast and osteoclast metabolism. The present study was performed to investigate the effects of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) on the expression of inducible NO-synthase (iNOS) and to measure high-output production of NO by primary rat osteoblasts and osteoblastic cell lines ROS 17/2.8, MC3T3-E1 and MG-63. In addition, we have investigated if NO may mediate some of the effects of these cytokines on osteoblast metabolism. Northern blots and immunocytochemistry revealed time-dependent iNOS messenger RNA and protein expression in primary rat osteoblasts in response to cytokine treatment. Reverse transcription polymerase chain reaction amplified an 807-base pair (bp) product from ROS 17/2.8 cells, which had a size and restriction enzyme-cut pattern identical to that predicted for authentic rat iNOS. Nitrite accumulation in culture medium was induced by IFN-gamma in a time- and dose-dependent manner and inhibited by cotreatment with inhibitors of NOS activity and by dexamethasone. IL-1 beta, TNF-alpha, and bacterial lipopolysaccharide were found to have weak stimulatory effects on nitrite production on their own. However, IL-1 beta and TNF-alpha showed strong synergy with IFN-gamma, but, surprisingly, lipopolysaccharide was found to exert potent inhibitory effects on IFN-gamma-induced nitrite synthesis. Basal production of nitrite and induction of its synthesis was similarly observed with primary rat osteoblasts as well as ROS 17/2.8, MC3T3-E1, and MG-63 cell lines. Cytokine-induced NO production significantly reduced osteoblast activity, as was evidenced by inhibition of DNA synthesis, cell proliferation, alkaline phosphatase activity, and osteocalcin production. The results provide evidence for a basal expression of iNOS activity and show that the iNOS messenger RNA, protein, and enzyme activity are all induced by cytokines across the species. The data further suggest that osteoblast-derived NO may have an important role in mediation of localized bone destruction associated with inflammatory bone diseases such as rheumatoid arthritis.
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PMID:Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity. 758 94

Macrophages can become activated to kill both tumor cells and a variety of microbes. Results here show that synthesis of nitric oxide (NO), a mediator of many macrophage cytotoxic functions, was greatly increased when cells of the mouse macrophage cell line RAW 264.7 were costimulated with bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), compared to LPS alone. This increase paralleled increases in cytotoxicity. Northern analysis showed that increased production of NO was preceded by markedly enhanced expression of mRNA for the inducible form of macrophage NO synthase (mac-NOS), which catalyzes the synthesis of NO. Cycloheximide inhibited the induction of mac-NOS mRNA by IFN-gamma and LPS, indicating that expression of this mRNA required de novo protein synthesis. Elevated expression of mac-NOS mRNA was not due to an increase in its stability. Rather, the combination of IFN-gamma and LPS induced a much higher rate of transcription of the mac-NOS gene than did stimulation with LPS alone. These results provide one explanation of why priming and triggering stimuli, such as IFN-gamma and LPS, respectively, synergistically activate macrophages and may be applicable to explaining how IFN-gamma augments NO-dependent microbicidal activity in macrophages as well.
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PMID:Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. 767 12

Both nitric oxide and prostaglandins are potent paracrine mediators of intercellular communication. An endotoxin-lipopolysaccharide (LPS) inducible form of nitric oxide synthase (mac-NOS) has recently been cloned from murine macrophages. An inducible prostaglandin synthase (TIS10/PGS-2), cloned from 3T3 cells, is also induced in LPS-activated macrophage. Because of the wide range of ligands that induce primary response genes in 3T3 cells, the ease of studying chimeric promoter constructs in 3T3 cells, and the importance of both nitric oxide and prostaglandins as paracrine mediators, we examined expression of mac-NOS in 3T3 cells. Tetradecanoyl phorbol-13-acetate (TPA), forskolin, platelet-derived growth factor, fibroblast growth factor, and serum all induce mac-NOS expression in Swiss 3T3 cells. Thus the mac-NOS gene can respond to a far wider range of inducers than previously suspected. mac-NOS is a primary response gene; cycloheximide does not block induction. TPA-induced mac-NOS and TIS10/PGS-2 mRNA accumulation patterns are similar. LPS is a potent inducer of mac-NOS in Swiss 3T3 cells but cannot induce TIS10/PGS-2. In contrast, v-src expression induces TIS10/PGS-2 message, but not iNOS message in a BALB/c 3T3 cell line containing a temperature-sensitive v-src gene. Dexamethasone (DEX) prevents induction of TIS10/PGS-2, but not most other primary response genes. DEX also blocks mac-NOS induction in Swiss 3T3 cells. The inducible TIS10/PGS-2 and mac-NOS genes, responsible for the production of two distinct paracrine agents, appear to share many regulatory features in 3T3 cells.
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PMID:"Macrophage" nitric oxide synthase is a glucocorticoid-inhibitable primary response gene in 3T3 cells. 769 32

The promoter region of the mouse gene for macrophage-inducible nitric oxide synthase (mac-NOS; EC 1.14.13.39) has been characterized. A putative TATA box is 30 base pairs upstream of the transcription start site. Computer analysis reveals numerous potential binding sites for transcription factors, many of them associated with stimuli that induce mac-NOS expression. To localize functionally important portions of the regulatory region, we constructed deletion mutants of the mac-NOS 5' flanking region and placed them upstream of a luciferase reporter gene. The macrophage cell line RAW 264.7, when transfected with a minimal promoter construct, expresses little luciferase activity when stimulated by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), or both. Maximal expression depends on two discrete regulatory regions upstream of the putative TATA box. Region I (position -48 to -209) increases luciferase activity approximately 75-fold over the minimal promoter construct. Region I contains LPS-related responsive elements, including a binding site for nuclear factor interleukin 6 (NF-IL6) and the kappa B binding site for NF-kappa B, suggesting that this region regulates LPS-induced expression of the mac-NOS gene. Region II (position -913 to -1029) alone does not increase luciferase expression, but together with region I it causes an additional 10-fold increase in expression. Together the two regions increase expression 750-fold over activity obtained from a minimal promoter construct. Region II contains motifs for binding IFN-related transcription factors and thus probably is responsible for IFN-mediated regulation of LPS-induced mac-NOS. Delineation of these two cooperative regions explains at the level of transcription how IFN-gamma and LPS act in concert to induce maximally the mac-NOS gene and, furthermore, how IFN-gamma augments the inflammatory response to LPS.
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PMID:Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. 769 52

The free radicals nitric oxide (NO) and superoxide (O2-) are known to react to form peroxynitrite (ONOO-), a potentially more injurious species. Here we compared the inhibitory effects of ONOO- and NO on mitochondrial respiration in J774.2 macrophages. In addition, using uric acid, a potent scavenger of ONOO-, we investigated the potential involvement of endogenous ONOO- in the inhibitory effects of bacterial lipopolysaccharide (LPS) and gamma-interferon (IFN) on mitochondrial respiration. The NO donors S-nitroso-N-acetyl-DL-penicillamine (SNAP, 1 mM) or diethylamine NONOate (DN, 1 mM) inhibited cellular respiration by approximately 30% over 24h. Equimolar amounts of ONOO- caused a more pronounced inhibition of cell respiration. There was a synergistic effect between the O2- generator pyrogallol (10 microM-1 mM) and the NO donor SNAP (1 mM) in inhibiting mitochondrial respiration. The ONOO- scavenger uric acid (UA, 1 mM) did not prevent the decrease in viability in response to SNAP, DN or pyrogallol, but significantly prevented the decrease in cell viability in response to ONOO-, to the combination of SNAP and pyrogallol, and to SIN-1, a compound that simultaneously generates NO and O2-. The decrease in mitochondrial respiration in response to LPS and IFN was also inhibited by UA as well as by NG-methyl-arginine, an inhibitor of NOS. Thus, ONOO- is a more potent suppressant of mitochondrial respiration than NO and endogenous formation of ONOO- appears to be involved in the cytotoxicity associated with immune stimulation.
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PMID:Endogenous peroxynitrite is involved in the inhibition of mitochondrial respiration in immuno-stimulated J774.2 macrophages. 773 45


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